This invention relates to novel narcotic antagonist compounds, compositions containing them and methods of using them.
The opioid analgesics (for example, morphine), although effective against severe pain, are not entirely free of risk. Since the drugs can produce euphoric effects in the user, they are often abused, and frequent use can lead to physical and/or psychological dependence. The addict who continuously uses the drug develops a significant tolerance to its euphorigenic effects and must constantly increase the dose to maintain a "high". Tolerance, however, is not absolute. Even in tolerant individuals, a dose exists which is capable of producing death from respiratory depression.
Certain drugs have been found which are useful for neutralizing or "antagonizing" the effects of narcotic drugs. These drugs, termed narcotic antagonists, have widely varying actions. Some antagonists, such as naloxone, are pure antagonists because they produce none of the effects associated with the opioid analgesics. Others, such as nalorphine or propiram, produce some of the effects of the opioid analgesics in addition to their powerful antagonistic actions.
The antagonists are extremely useful in treatment of patients suffering from opioid poisoning (i.e., overdose). Administration of narcotic antagonists can produce dramatic reversal of severe narcotic-induced respiratory depression. Often, a pure antagonist or one with very minimal agonistic activity is desired for this type of use; a mixed agonist-antagonist may only further decrease respiration that has been depressed by narcotic overdose.
On the other hand, it may in some instance be desired to reverse respiratory depression without also reversing the desirable analgetic effects of the opiate. In such cases, a mixed agonist-antagonist is especially useful.
The narcotic antagonists have other uses as well. They may, for example, be used to modify patterns of compulsive drug abuse. The antagonists act to attenuate or even entirely block the effects of the opioids and thus interfere with the reinforcing or satisfying properties of the drugs. Some mixed agonist-antagonists may have yet a further use as non-addictive analgesics.
Quite a few narcotic antagonists are known in the art. U.S. Pat. No. 3,332,950 to Blumberg et al. (1967) teaches that compounds of the following formula are useful as narcotic antagonists: ##STR2## where R is 3'-methyl-2'-butenyl, cyclopropylmethyl, or cyclobutylmethyl.
Compounds of the formula ##STR3## where R is allyl or cyclopropylmethyl, are taught to have antagonistic activity in E. F. Hahn, et al., J. Med. Chem. 18, 259 (1975).
A process for preparing compounds of the formula ##STR4## where Y is cyclobutyl or cyclopropyl and Z is ##STR5## or O is disclosed in Canadian Pat. No. 913,077, dated Oct. 24, 1972.
G. Horvath et al., Magy. Kem. Foly. 79, 429 (1973), discloses narcotic analgetics without antagonist activity of the formula ##STR6##
U.S. Pat. No. 3,162,639 to Fishman (1964) teaches compounds of the formula ##STR7## where R is H or CH.sub.3. These compounds are disclosed to be analgesics and are not taught to have antagonistic activity.
With the ever-increasing incidence of drug abuse in our society, the need for new narcotic antagonists is clear. New antagonists which are safer and longer-acting than those known in the art or which exhibit new degrees of effectiveness are especially needed.